The most important mechanism of microbial resistance to xcex2-lactam antibiotics is the bacterial production of xcex2-lactamases, enzymes which hydrolytically destroy xcex2-lactam antibiotics, such as penicillins and cephalosporins. This type of resistance can be transferred horizontally by plasmids that are capable of rapidly spreading the resistance, not only to other members of the same strain, but even to other species. Due to such rapid gene transfer, a patient can become infected with different organisms, each possessing the same xcex2-lactamase.
xcex2-lactamase enzymes have been organized into four molecular classes: A, B, C and D based on amino acid sequence. Class A, includes RTEM and the xcex2-lactamase of Staphylococcus aureus, class C, includes the lactamase derived from P99 Enterobacter cloacae, and class D are serine hydrolases. Class A enzymes have a molecular weight of about 29 kDa and preferentially hydrolyze penicillins. The class B lactamases are metalloenzymes and have a broader substrate profile than the proteins in the other classes. Class C enzymes include the chromosomal cephalosporinases of gram-negative bacteria and have molecular weights of approximately 39 kDa. The recently recognized class D enzymes exhibit a unique substrate profile that differs significantly from the profile of both class A and class C enzymes.
The class C cephalosporinases, in particular, are responsible for the resistance of gram-negative bacteria to a variety of both traditional and newly designed antibiotics. The Enterobacter species, which possesses a class C enzyme, is now the third greatest cause of nosocomial infections in the United States. This class of enzymes often has poor affinities for inhibitors of the class A enzymes, such as clavulanic acid, a commonly prescribed inhibitor, and to common in vitro inactivators, such as 6-xcex2-iodopenicillanate.
One strategy for overcoming this rapidly evolving bacterial resistance is the synthesis and administration of xcex2-lactamase inhibitors. Frequently, xcex2-lactamase inhibitors do not possess antibiotic activity themselves and are thus administered together with an antibiotic. One example of such a synergistic mixture is xe2x80x9cAUGMENTINxe2x80x9d (a registered trademark of Smithkline Beecham Inc), which contains the antibiotic amoxicillin and the xcex2-lactamase inhibitor, clavulanic acid.
Thus, there is a continuing need for novel xcex2-lactamase inhibitors.
The present invention provides novel penicillin derivatives that are potent inhibitors of xcex2-lactamase enzymes. Accordingly, the invention provides a compound of formula (I): 
wherein
R1 and R2 are each independently hydrogen, (C1-C10)alkyl, (C3-C8)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, xe2x80x94COORa, xe2x80x94CONRbRc, cyano, xe2x80x94C(xe2x95x90O)Rd, xe2x80x94ORe, aryl, heteroaryl, oxazolidinyl, isoxazolidinyl, morpholinyl, xe2x80x94S(O)mRf, xe2x80x94NRgRh, azido, or halo;
R3 is (C3-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkanoyl, (C3-C8)cycloalkyl, aryl, heteroaryl, aryl(C1-C10)alkyl, heteroaryl(C1-C10)alkyl, or xe2x80x94CH2Ri, wherein Ri is halo, cyano, cyanato, xe2x80x94ORj, xe2x80x94NRkRl, azido, xe2x80x94SRm, or (C3-C8)cycloalkyl;
R4 is hydrogen, (C1-C10)alkyl, (C3-C8)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, aryl, or heteroaryl;
m and n are each independently 0, 1, or 2;
each Ra-Rf is independently hydrogen, (C1-C10)alkyl, (C3-C8)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, aryl, heteroaryl, oxazolidinyl, isoxazolidinyl, or morpholinyl;
each Rg or Rh is independently hydrogen, (C1-C10)alkyl, (C3-C8)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkanoyl, aryl, benzyl, phenethyl, heteroaryl oxazolidinyl, isoxazolidinyl, or morpholinyl; or Rg and Rh together with the nitrogen to which they are attached are triazolyl, imidazolyl, oxazolidinyl, isoxazolidinyl, pyrrolyl, morpholino, piperidino, pyrrolidino, pyrazolyl, indolyl, or tetrazolyl;
Rj is hydrogen, (C1-C10)alkyl, (C3-C8)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, xe2x80x94C(xe2x95x90O)N(Rp)2, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, or (C1-C10)alkanoyl, wherein each Rp is independently hydrogen, (C1-C10)alkyl, aryl, benzyl, phenethyl, or heteroaryl;
each Rk or Rl is independently hydrogen, (C1-C10)alkyl, (C3-C8)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkanoyl, xe2x80x94C(xe2x95x90O)N(Rq)2, aryl, benzyl, phenethyl, heteroaryl oxazolidinyl, isoxazolidinyl, or morpholinyl, wherein each Rq is independently hydrogen, (C1-C10)alkyl, aryl, benzyl, phenethyl, or heteroaryl; or Rk and Rl together with the nitrogen to which they are attached are triazolyl, imidazolyl, oxazolidinyl, isoxazolidinyl, pyrrolyl, morpholino, piperidino, pyrrolidino, pyrazolyl, indolyl, or tetrazolyl; and
Rm is hydrogen, (C1-C10)alkyl, (C3-C8)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, cyano, aryl, benzyl, phenethyl, heteroaryl, oxazolidinyl, isoxazolidinyl, or morpholinyl;
wherein any (C1-C10)alkyl, (C3-C8)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkanoyl, aryl, benzyl, phenethyl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, oxazolidinyl, isoxazolidinyl, or morpholinyl of R1-R4, Ra-Rm, or Rp-Rq, may optionally be substituted with 1, 2, or 3 Z; and each Z is independently halo, nitro, cyano, hydroxy, (C1-C10)alkyl, (C3-C8)cycloalkyl, (C1-C10)alkoxy, (C1-C10)alkanoyl, (C2-C10)alkanoyloxy, trifluoromethyl, aryl, aryloxy, heteroaryl, or xe2x80x94SRn, wherein Rn is hydrogen, (C1-C10)alkyl, (C3-C8)cycloalkyl, aryl, benzyl, phenethyl, or heteroaryl;
and further wherein any aryl, aryloxy, heteroaryl, benzyl, or phenethyl of Z may optionally be substituted with 1, 2, or 3 substituents selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C10)alkyl, (C3-C8)cycloalkyl, (C1-C10)alkoxy, (C1-C10)alkanoyl, (C2-C10)alkanoyloxy, benzyloxy, 4-methoxybenzyloxy, and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.